Antifungals Flashcards
Classification of Mycoses
System (potentialy life threatening)
Superficial
Antifungal Targets
Targets:
membranes (ergosterol)
nucleic acids
cell wall
Drugs for systemic fungal infections
Amphotericin B
Flucytoisne
Imidazoles (fluconazole, itraconazole, voriconazole)
Capsofungin
Amphotericin B
Effective for most serious systemic mycoses especially those are life threatening immediately
Gold standard for anti-fungal effectiveness by which other drugs are judged
Side effects: so use for proven of highly suspected systemic infections (Total cumulative dose is important for reasons permanent renal toxicity)
fever, nausea, vomiting, headache, chills, hypotension, hypokalemia, tachypnea, 90% with nonpermanent nephrotoxicity (permanent renal damage occurs depending of total dose), reversible hypochromic, normocytic anemia
Only fungistatic at serum levels in human
MOA Amphotericin B
Binds to ergosterol in membrane causes membrane leakiness (causes holes)
Flucytosine (5-FC)
Serious infections: Candida, Cryptococcus
Used in conjunction (synergistic) with amphotericin B
Side effects: nausea, vomiting, diarrhea, enterocolitis, Leukopnia thrombocytopenia, extreme caution with renal insufficiency or bone marrow depression, reversible elevated hepatic enzymes
Fluctyosine (5-FC)
fungal cytosine deaminase which converts cytosine permease to 5 FU
which inhibits DNA synthesis
Triazoles
fluconazole
voriconazole
itraconazole
Triazole MoA and Side effects
Inhibit 14 alpha sterol demethylase, fungal cytochrome P450 that converts lanosterol to erosterol
Net effect is inhibition of ergosterol synthesis
This is slower onset mechanism
Side effects: nausea, vomiting, rash, diarrhea, headache, mild hepatotoxicity (discontinue with onset of liver dysfunction)
Inhibits metabolism of several other drugs (CYP3A and 2C families) because inhibit CYP450s
Fluconazole
Cryptococcus
Candida (many sites including CNS and urinary)
most C. albicans, some C. glabrata, not C. krusei (narrow spectrum of Candida)
CNS penetration: yes
Active drug in urine
Lowest incidence of hepatotoxicity among the azole antifungals
Itraconazole
Blastomyces
Histoplasma
Candia (esophagus and oropharynx but not CNS and urinary)
More albicans and glabrata and some C. krusei
No CNS penetration or active drug in urine
Contraindications: do not give with other drugs that are metabolized by CYP3A4
can cause potential for severe CV events including death
Voriconazole
Aspergillus
Candida (not urinary)
covers many species including glabrata and krusei
Limited CNS penetration and no active drug in urine
Side effects: visual distrubances (30%), phosensitive component to rash
Anti-fungals that Target Cell Wall
caspofungin
Caspofungin
Treat invasive Aspergillus (intolerant to other drugs), Candida (esophageal and systemic and broad coverage of glabra and krusei)
MOA: inhibit fungal cell wall synthesis by noncompeitively blocking synthesis of B(1,3)-D-glucan in filamentous fungi
No cross resistance with imidazoles and triazoles
Side effects: fever, nausea, flushing, phlebitis at injection site
Treatment of Superficial Mycoses
Nystatin
Imidazoles (fluconazole, miconazole, clotrimazole, itraconazole)
Opthalmic : natamycin
Fluconazole
Candida infections (vaginal, urinary track, oropharynx) Oral not topical
Miconazole
Topical: creams/suppositories for vaginal Candida
Clotrimazole
Candia topical use (oral troches or vaginal creams/solutions) Side effect or oral troches: abnormal liver function test
Itraconazole
Candida: oropharyngeal and esophageal (oral not topical)
Nystatin
Mechanism similar to amphotericin B (effecitve against -azole-resistant strains)
Topical use for Candida (skin, mucous membrane, vaginal)
Oral use for GI tract Candida (not absorbed systemically)
Side effects: oral has GI distress and bad taste
Amphotericin B
Topical
Cutaneous or mucosal Candida (not for dermatophytes
Treatment of Opthalmic fungal infections
Natamycin- opthalmic infections
Mechanism similar to amphotericin B
not systemically because too toxic
toxicity: conjunctival chemosis and hyperemia
Topical Treatment for Dermatophytes (Tinea pedis, Tinea cruris, Tinea corporis)
Miconazole, clotrimazole
Tolnaftate
Terbinafine
Ciclopirox (nail laquer)
Topical Treatment for Fungal Nail Infections
Ciclopirox- FDA approved topical for mld to moderate fungal nail infections
mechanism: inhibit metal dependent fungal enzymes by metal chelation
Terbinafine
Oral drugs
12 week therapy for nail infections
deposit and stay in tissue for a long time
also shorter duration of therapy for tinea capitis
MOA: blocks early in pathway from blocking squalene to 2,3-oxidosqualene upstream of ergosterol and fungicidal because squalene accumulates and disrupt fungal cell membrane
Side effects: diarrhea, dyspepsia, abdominal pain
Griseofulvin
for recalcitrant dermatophytic infections of skin, hair, nails
Therapy for tinea capitis
Mechanism: interfere with microtubule function/mitotic spindle/mitosis
Side effects: contraindicated in those with prophyria and advanced liver disease, inreased metabolism of several drugs (CYP inducer), Use with caution with those with penicillin allergies
Itraconazole
Oral therapy for fungal toenail infections
Side effects: nausea, vomiting, rash, diarrhea, headache, edema, inhibits metabolism of many drugs, discontinue if signs of liver dysfunction
Oral Antifungal dermatophytes
Itraconazole
Griseofulvin
Terbinafine
